PLAURpolymorphisms and lung function in UK smokers

Abstract

BackgroundWe have previously identified Urokinase Plasminogen Activator Receptor (PLAUR) as an asthma susceptibility gene. In the current study we tested the hypothesis that PLAUR single nucleotide polymorphisms (SNPs) determine baseline lung function and contribute to the development of Chronic Obstructive Pulmonary Disease (COPD) in smokers.Methods25 PLAUR SNPs were genotyped in COPD subjects and individuals with smoking history (n = 992). Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV1, FEV1/FVC) in all smokers. Genotype frequencies were compared in spirometry defined smoking controls (n = 176) versus COPD cases (n = 599) and COPD severity (GOLD stratification) using logistic regression.ResultsFive SNPs showed a significant association (p < 0.01) with baseline lung function; rs2302524(Lys220Arg) and rs2283628(intron 3) were associated with lower and higher FEV1 respectively. rs740587(-22346), rs11668247(-20040) and rs344779(-3666) in the 5'region were associated with increased FEV1/FVC ratio. rs740587 was also protective for COPD susceptibility and rs11668247 was protective for COPD severity although no allele dose relationship was apparent. Interestingly, several of these associations were driven by male smokers not females.ConclusionThis study provides tentative evidence that the asthma associated gene PLAUR also influences baseline lung function in smokers. However the case-control analyses do not support the conclusion that PLAUR is a major COPD susceptibility gene in smokers. PLAUR is a key serine protease receptor involved in the generation of plasmin and has been implicated in airway remodelling.

Evidence of a genetic contribution to lung function decline in asthma

“…34 In addition to the genetic association between lung function decline in asthmatic subjects, we have also demonstrated that PLAUR is a susceptibility gene for the impairment of lung function in smokers. 35 As commented above, ESR1 might influence plasmin generation, and a recent article has also implicated ADAM proteins in mediating PLAUR activation by using the ADAM inhibitors TNF-a protease inhibitor (TAPI)-0, and TAPI-1, 36 suggesting there might be functional relationship between the mechanisms underlying the associations with ADAM33, ESR1, and PLAUR.…”

Combined Analysis of EPHX1, GSTP1, GSTM1 and GSTT1 Gene Polymorphisms in Relation to Chronic Obstructive Pulmonary Disease Risk and Lung Function Impairment

“…The EPHX1 enzyme activity has been detected in all tissues, and the highest concentrations have been found in lung, liver, kidney, gonads, and epithelial cells [40]. Several recent studies were focused on the relationship between gene polymorphisms and lung function in COPD patients, smokers and in general population with controversial results [41][42][43][44][45][46][47].…”

Do smokers have greater risk of delayed and non-union after fracture, osteotomy and arthrodesis? A systematic review with meta-analysis

“…The effect of smoking is likely to be linked to smoking-related comorbidities, for example, chronic obstructive pulmonary disease. [63][64][65] There are also considerations regarding secondhand smoke; research has established that there is a link with biomarkers of cardiovascular disease risk in passive smokers. 66 An interesting question is whether smokers develop a larger zone of injury than non-smokers which could be mediated by hypoxia and hyperoxidant stress.…”